The present invention relates to a novel, industrially superior process for the production of 1,4-substituted cyclic amine compound such as those disclosed in WO 98/43956 which are useful as pharmaceuticals and to intermediates thereof.
Among the 1,4-substituted cyclic amine compounds disclosed in WO 98/43956, indole compounds which are target compounds of the present invention have been prepared primarily by synthesizing corresponding indoline compounds and then oxidizing the indoline compounds.
This is because the NH group in the indoles has low reactivity and, therefore, it is difficult to directly add a side chain thereto.
In the oxidation of the indoles, various oxidizing agents can be used, and manganese dioxide is frequently used. However, the oxidation using manganese dioxide is rate-limited by stirring because it is a heterogeneous reaction, and therefore a large-volume treatment on an industrial scale is hardly achieved. In addition, since the reactivity of the oxidation depends on the degree of activation of the catalyst, the reaction usually takes several hours to complete, and in some cases, takes one day or longer. Moreover, when manganese dioxide is re-used repeatedly, its activity decreases, and this may have a large effect on production costs.
On the other hand, other oxidizing agents, such as permanganates, hydrogen peroxide, nitric acid, lead tetraacetate, mercuric acetate, potassium nitrosodisulfate (Fremy""s salt), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and tetrachldrobenzoquinone (chloranil) have good reactivity. However, with such oxidizing agents, there have been problems such as the occurrence of adverse side reactions due to their high activities, poor storage properties, toxicity and poor safety, and generally being expensive, and therefore are not always suitable for industrial applications.
In these situations, the present inventors have conducted extensive studies for the purpose of developing a novel production process which is useful from the viewpoints of stability of raw materials, production costs, ease of operation (e.g., workability, safety, non-toxicity), purity of the final product and so on.
As a result, the inventors have found that the process described in detail hereinbelow can solve the above-mentioned problems at a stroke and have accomplished the present invention.
Accordingly, the object of the present invention is to provide a novel process for the production of indole compounds which are useful as fine chemicals such as pharmaceuticals, and to provide intermediates for the process.
Herein, the indole compound (I) according to the present invention is represented by the following formula: 
wherein R1 represents hydroxymethyl group, carboxyl group, a lower alkoxycarbonyl group or a carbamoyl group in which the nitrogen atom may be substituted; R2 represents an aryl. group which may be substituted, a heteroaryl group which may be substituted or a benzoheteroaryl group which may be substituted; and n is 0 or an integer from 1 to 6.
In the above definition, the hydroxymethyl group refers to a group represented by the formula xe2x80x94CH2OH, and the carboxyl group refers to a group represented by the formula xe2x80x94COOH.
The lower alkoxycarbonyl group refers to a group represented by the formula xe2x80x94COOR, wherein R represents a linear or branched lower alkyl group having 1 to 6 carbon atoms.
The carbamoyl group which may be substituted refers to a carbamoyl group in which the nitrogen atom may be substituted by a lower alkyl group or the like, wherein the nitrogen atom may be included in a cyclic amine. Specifically, for example, carbamoyl (xe2x80x94CONH2), N-methylcarbamoyl (xe2x80x94CONHCH3), N,N-dimethylcarbamoyl (xe2x80x94CON(CH3)2), N-ethylcarbamoyl (xe2x80x94CONHC2H5), N,N-diethylcarbamoyl (xe2x80x94CON(C2H5)2), N-methyl-N-ethylcarbamoyl (xe2x80x94CON(CH3)C2H5), N-propylcarbamoyl (xe2x80x94CONHC3H7), 1-pyrrolidinylcarbonyl, 1-pyrazolynylcarbonyl, 1-piperidylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl and 4-thiomorpholinylcarbonyl groups. Among these, N-methylcarbamoyl, N-ethylcarbamoyl or N-propylcarbamoyl group is preferred from the viewpoints of pharmacological activity and safety.
The aryl group which may be substituted refers to a group derived from an aromatic ring such as a phenyl or naphthyl group, which may not be substituted or have a substituent. Examples of the substituent include the following members.
(1) halogen atom;
(2) hydroxyl group;
(3) a lower alkyl group;
(4) a lower alkoxy group;
(5) a lower alkoxyalkoxy group;
(6) an amino group in which the nitrogen atom may be substituted;
(7) nitro group;
(8) cyano group;
(9) formyl group;
(10) a lower acyl group;
(11) an aromatic acyl group;
(12) a heteroarylcarbonyl group;
(13) a halogenated lower alkyl group;
(14) a lower alkoxyalkoxy group;
(15) a hydroxy(lower)alkyl group;
(16) a hydroxy(lower)alkoxy group;
(17) a lower alkoxycarbonyl group;
(18) a carbamoyl group in which the nitrogen atom may be substituted;
(19) a lower alkylsulfonyl group;
(20) a lower alkylsulfinyl group;
(21) a sulfamoyl group in which the nitrogen atom may be substituted;
(22) a lower acylamino group;
(23) a lower alkoxycarbonylamino group;
(24) a lower alkylsulfonylamino group;
(25) an arylsulfonylamino group in which the nitrogen atom may be substituted;
(26) a lower alkylsulfonyloxy group;
(27) an alkylenedioxy group;
(28) an aralkyl group;
(29) an aralkyloxy group; and
(30) a tri(lower)alkylsilyl group.
Among these, a halogen atom is more preferred. Specific examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms. Chlorine or fluorine atom is more preferable with regards to pharmacological activity and safety.
The heteroaryl group which may be substituted refers to a group which is derived from a hateroaromatic ring and it may not be substituted or have a substituent. Specific examples thereof include furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl and pyrimidinyl groups. The substituent includes those described for the aryl group which may be substituted.
The benzoheteroaryl group which may be substituted refers to a group which is derived from a benzoheteroaromatic ring and may not be substituted or have a substitutent. Specific examples thereof include indolyl, benzothiazolyl, benzoimidazolyl, quinolyl, isoquinolyl, phthaladinyl, quinoxanyl and quinazolynyl groups. The substituent includes those described for the aryl group which may be substituted.
Herein, more specifically as the indole compound (I) according to the present invention, the following compounds may be proposed, but is not limited thereto.
(1) 1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-methylcarbamoylmethyl indole;
(2) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-(N,N-dimethylcarbamoyl)methyl indole;
(3) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methylcarbamoylmethyl indole;
(4) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ethylcarbamoylmethyl indole; and
(5) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-piperidinylcarbonyl)methyl indole.
Sequentially, the 2-halogenated indole compound (II) according to the present invention is represented by the following formula: 
wherein X represents a halogen atom; and R1, R2 and n have the same meanings as defined above.
The 2-halogenated indole compound (II) is a novel compound and is useful as an intermediate in the novel process for the production of the indole compound (I) of the present invention.
More specifically as the 2-halogenated indole compound (II), the following compounds may be proposed, but is not limited thereto:
(1) ethyl [1-[1-(2-fluorophenethyl)piperidin-4-yl]-2-chloroindol-6-yl]acetate;
(2) ethyl [1-[1-(2-fluorophenethyl)piperidin-4-yl]-2-bromoindol-6-yl]acetate;
(3) ethyl [1-[1-(3-fluorophenethyl)piperidin-4-yl]-2-chloroindol-6-yl]acetate;
(4) ethyl [1-[1-(3-fluorophenethyl)piperidin-4-yl]-2-bromoindol-6-yl]acetate;
(5) ethyl [1-[1-(4-fluorophenethyl)piperidin-4-yl]-2-chloroindol-6-yl]acetate;
(6) ethyl [1-[1-(4-fluorophenethyl)piperidin-4-yl]-2-bromoindol-6-yl]acetate;
(7) ethyl [1-[1-(2-chlorophenethyl)piperidin-4-yl]-2-chloroindol-6-yl]acetate;
(8) ethyl [1-[1-(2-chlorophenethyl)piperidin-4-yl]-2-bromoindol-6-yl]acetate;
(9) ethyl [1-[1-(3-chlorophenethyl)piperidin-4-yl]-2-chloroindol-6-yl]acetate;
(10) ethyl [1-[1-(3-chlorophenethyl)piperidin-4-yl]-2-bromoindol-6-yl]acetate;
(11) ethyl [1-[1-(4-chlorophenethyl)piperidin-4-yl]-2-chloroindol-6-yl]acetate; and
(12) ethyl [1-[1-(4-chlorophenethyl)piperidin-4-yl]-2-bromoindol-6-yl]acetate.
Further, the 2-oxoindoline compound (III) according to the present invention is represented by the following formula: 
wherein R1, R2 and n have the same meanings as defined above.
The 2-oxoindoline derivative (III) is a novel compound and is useful as an intermediate in the novel process for the production of the indole derivative (I) of the present invention.
More specifically as the 2-oxoindoline compound (III), the following compounds may be proposed, but is not limited thereto:
(1) ethyl [1-[1-(2-fluorophenethyl)piperidin-4-yl]-2-oxoindolin-6-yl]acetate;
(2) ethyl [1-[1-(3-fluorophenethyl)piperidin-4-yl]-2-oxoindolin-6-yl]acetate;
(3) ethyl [1-[1-(4-fluorophenethyl)piperidin-4-yl]-2-oxoindolin-6-yl]acetate;
(4) ethyl [1-[1-(2-chlorophenethyl)piperidin-4-yl]-2-oxoindolin-6-yl]acetate;
(5) ethyl [1-[1-(3-chlorophenethyl)piperidin-4-yl]-2-oxoindolin-6-yl]acetate; and
(6) ethyl [1-[1-(4-chlorophenethyl)piperidin-4-yl]-2-oxoindolin-6-yl]acetate.
Further, the 1,4-substituted 2-piperidylaminophenyl compound (IV) according to the present invention is represented by the following formula: 
wherein R1, R2 and n have the same meanings as defined above.
The 1,4-substituted 2-piperidylaminophenyl compound (IV) is a novel compound and is useful as an intermediate in the novel process for the production of the indole compound (I) of the present invention.
More specifically as the 1,4-substituted 2-piperidylaminophenyl compound (IV), the following compounds may be proposed, but is not limited thereto:
(1) ethyl 2-[1-(2-fluorophenethyl)piperidin-4-yl]aminobenzene-1,4-diacetate;
(2) methyl 2-[1-(3-fluorophenethyl)piperidin-4-yl]aminobenzene-1,4-diacetate;
(3) propyl 2-[1-(4-fluorophenethyl)piperidin-4-yl]aminobenzene-1,4-diacetate;
(4) ethyl 2-[1-(2-chlorophenethyl)piperidin-4-yl]aminobenzene-1,4-diacetate;
(5) methyl 2-[1-(3-chlorophenethyl)piperidin-4-yl]aminobenzene-1,4-diacetate; and
(6) propyl 2-[1-(4-chlorophenethyl)piperidin-4-yl]aminobenzene-1,4-diacetate.
Further, the 1,4-substituted 2-aminophenyl compound (V) according to the present invention is represented by the following formula: 
wherein R1 has the same meaning as defined above.
Further, the N-substituted 4-piperidone compound (VI) according to the present invention is represented by the following formula: 
wherein R2 and n have the same meanings as defined above.
Finally, the 1,4-substituted 2-nitrophenyl compound (VII) according to the present invention is represented by the following formula: 
wherein R1 has the same meaning as defined above.
Sequentially, the scheme of chemical reactions in the novel process for the production of an indole compound (I) according to the present invention is as follows. 
wherein R1, R2, X and n have the same meanings as defined above.
The production process is described in detail below with reference to the above scheme.
(1) Step 1
This step is for reducing a 1,4-substituted 2-nitrophenyl compound (VII), to give a 1,4-substituted 2-aminophenyl compound (V).
The reaction is not particularly limited and any conventional method for the reduction of a nitro group may be employed. However, a contact reduction method is preferred, since the reaction can be achieved efficiently with a high yield.
(2) Step 2
This step is for reductive amidation of the 1,4-substituted 2-aminophenyl compound (V) with a N-substituted 4-piperidone compound (VI), to give a 1,4-substituted 2-piperidylaminophenyl compound (IV).
The reaction may be performed, for example, in accordance with a method as described in the New Experimental Chemical Studies (xe2x80x9cShin Jikken Kagaku Kozaxe2x80x9d) 14-III, p.1380, published by Maruzen.
The reduction method or reducing agent to be used in the reaction is not particularly limited. For example, borane, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride can be used as the reducing agent.
The reaction can proceed more rapidly and with good selectivity in the presence of boron trifluoride/diethyl ether complex or a Lewis acid (e.g., titanium tetrachloride).
(3) Step 3
This step is for cyclizing the 1,4-substituted 2-piperidylaminophenyl compound (IV), to give a 2-oxoindoline compound (III).
The reaction may be performed by a conventional method under an acidic condition, for example in the presence of sulfuric acid, polyphospholic acid, hydrochloric acid, p-toluenesulfonic acid monohydrate or the like.
(4) Step 4
This step is for halogenating the 2-oxoindoline compound (III), to give a 2-haloganated indole compound (II).
The reaction may be performed using a conventional halogenating agent used for organic synthesis. Specific examples of the halogenating agent include phosphoryl chloride (phosphorous oxychloride), thionyl chloride, sulfuryl chloride, phosphorous trichloride, phosphorous pentachloride, oxalyl chloride, thionyl bromide and phosphorous tribromide.
(5) Step 5
This step is for reducing the 2-haloganated indole compound (II), to give an objective indole compound (I).
As in the case of Step (1), any conventional method for reducing a halogen atom may be employed in the reaction, but a contact reduction method is preferred because the reaction can be achieved effectively and with a good yield.
The objective indole compound (I) may be purified by a conventional method such as column chromatography. The compound may also be purified by crystallization. In this case, the solvent for the crystallization is not particularly limited and any conventional solvent may be used. In particular, a solvent selected from the group consisting of heptane, ethanol, isopropyl acetate, n-propanol and isopropanol, or a mixture thereof may be used to give the compound in a good yield and at a high purity. In this case, examples of the mixed solvent include heptane/ethanol, heptane/isopropyl acetate, heptane/n-propanol and heptane/isopropanol.